Alpha Lipoic acid is taken up by cells and is reduced to a pharmacologically active dithiol form in several physiological reactions. However this active dithiol form is effluxed out of the cell rapidly decreasing the effectiveness of α-Lipoic acid.
Various mechanisms have been devised to enhance the retention of the active dithiol form within the cell. One such approach is a structurally modified version of α-Lipoic acid called LA-plus, chemically N-[2-(dimethylamino)ethyl]-1,2-dithiolane-3-pentanamide monohydrochloride, which is represented by the formula

The protonated form of the corresponding derived dithiol molecule under physiological conditions is more efficiently retained within the cell and performs much better in physiological reactions than the parent α-Lipoic acid. This has been the subject of research papers (Sen, Chandan K; Tirosh, Oren; Roy, Sashwati; Kobayashi, Michael S; Packer, Lester; Biochemical and Biophysical research Communications, (1998), 247, 223–228).
These workers demonstrated that the uptake of LA-Plus was much higher in certain cells and also the intracellular amount of the corresponding dithiol form within the cell was much greater compared to α-Lipoic acid. Hence they came to the conclusion that LA-Plus is an improved form of Lipoic acid with enhanced therapeutic potential.
The (R)-form of LA-Plus described in the above work was synthesized by the reaction of Lipoic acid to which three equivalents of N,N-dimethylethylenediamine were added followed by N-hydroxysuccinimide. Dicylohexylcarbodiimide was subsequently added and the reaction time was one day. The product was extracted into the aqueous phase using hydrochloric acid and extracted into chloroform after basification of the aqueous phase using sodium hydroxide. This organic phase was dried, filtered and evaporated to dryness. The residue was redissolved in dichloromethane and hydrogen chloride gas was passed through the organic solvent up to saturation. The dichloromethane solvent was evaporated and the HCl salt of N,N-dimethyl-N″-2-amidoethyl-lipoate was precipitated using anhydrous ether.
It should be noted that the preparation LA-Plus hydrochloride involves extraction and re-extraction of the product in and out of aqueous/organic media. Also it involves the passage of hydrogen chloride gas, which is corrosive and difficult to use. Several solvents such as chloroform, methylene chloride, and dry diethyl ether are employed in the process.
Hence the synthesis of LA-plus as described in prior art is involved and not easily adaptable to large-scale operations (Sen, Chandan K; Tirosh, Oren; Roy, Sashwati; Kobayashi, Michael S; Packer, Lester; Biochemical and Biophysical research Communications, (1998), 247, 223–228).
More particularly, the product, both the racemeic (±)-LA-Plus hydrochloride and chiral (R)-LA-Plus hydrochloride forms are not good solids. They were also found to be hygroscopic and not easily handled during transfer and other operations.
In spite of the difficulty of handling LA Plus hydrochloride, applications involving this hygroscopic salts have been claimed (U.S. Pat. No. 5,965,618, U.S. Pat. No. 6,090,842, WO 0180851). Hence there is a need for a new salt form of LA-plus base which would be a good solid, non-hygroscopic and easily handled for various operations.
The preparation and use of compositions containing Lipoic acid or its derivatives, including LA-plus, for nutraceutical and cosmetic applications is widely described in prior art for example in U.S. Pat. Nos. 6,743,433 and 6,365,623 that describe compositions for the treatment of acne; U.S. Pat. Nos. 6,387,945, 6,235,772 and 6,090,842 that describe Lipoic acid analogs. The preparations of the current invention were found to be similarly biologically active.